It is well known that many protein preparations intended for administration to humans require stabilizers to prevent denaturation, aggregation and other alternations to the proteins prior to the use of the preparation. Many protein preparations are particularly unstable in very dilute or highly concentrated solutions. This instability is manifested in the formation of soluble/insoluble aggregates, and is often increased when the protein preparation is stored, or shipped. A major challenge that exists in the field of protein drugs is in the development of formulations that maintain both protein stability and activity.
Immunoglobulins, in particular, are recognized as possessing characteristics that tend to form aggregates and particulates in solution; thus requiring filtration of these formulations prior to using them for intravenous injection. The formation of protein aggregates and particulates has long been a problem in the development of parenteral immunoglobulin products. There is a need in the art for a stable pharmaceutical formulation comprising an antibody.
WO 89/11297 discloses a lyophilized composition comprising a monoclonal immunoglobulin antibody of 1-25 mg/ml, 2-10% maltose, and sodium acetate, phosphate, or citrate buffer having a pH between 3.0 to 6.0.
Synagis™ (MedImmune) is a humanized monoclonal IgG1 antibody produced by recombinant DNA technology, directed to an epitope in the A antigenic site of the T protein of respiratory syncytial virus (RSV). Synagis™ is a composite of human (95%) and murine (5%) antibody sequences. Synagis™ is supplied as a sterile lyophilized product for reconstruction with sterile water for injection. Reconstituted Synagis™ is required to stand at room temperature for a minimum of 20 minutes until the solution clarifies. Reconstituted Synagis™ is to be administered by intramuscular injection only. Upon reconstitution, Synagis™ contains the following excipients: 47 mM histidine, 3.0 mM glycine and 5.6% mannitol and the active ingredient, IgG1 antibody, at a concentration of 100 milligrams per vial. (See Physicians' Desk Reference®, Medical Economic Company, Inc., Montvale, N.J.)
U.S. Patent Application Publication No. US 2001/0014326A1 discloses a pre-lyophilized antibody formulation containing 25 mg/ml anti-IgE antibody, 5 mM histidine, pH 6.0, 85 mM sucrose, and 0.01% polysorbate 20.
U.S. Pat. No. 6,171,586 discloses a stable aqueous pharmaceutical formulation comprising a therapeutically effective amount of an antibody not subjected to prior lyophilization, and acetate buffer from about pH 4.8 to about 5.5, a surfactant, and a polyol, wherein the formulation lacks a tonicifying amount of sodium chloride.
WO 97/45140 discloses a monoclonal antibody preparation of a humanized antibody against the CDw52 antigen, having a concentration of 100 mg/ml or greater, wherein the preparation is substantially free from aggregates.
Cleland, et al. (J. Pharm. Sci., 90:310-321 (2001)) disclose that a 360:1 molar ratio of lyoprotectant to protein is required for storage stability of a lyophilized monoclonal antibody.
There is a need for a stable, highly concentrated lyophilized antibody preparation for administration to a human, such antibody can be reconstituted within a short time and is suitable for parenteral administration, including intravenous, intramuscular, intraperitoneal, or subcutaneous injection.